The overall goals of this ongoing research project are to study the metabolism, excretion and persistence of long-acting narcotics, using methadone as a prototypic compound, in man, primarily in tolerant humans maintained on methadone, and in both naive and tolerant animals, and to study interactions between methadone and other drugs or agents whch may alter its disposition and thus its effects. New techniques using gas chromatography and mass spectrometry continue to be developed to carry out these studies. Specific recent objectives have been to apply our recently developed stable isotope technology for clinical investigation of the disposition of the separate active and inactive enantiomers in patients maintained on methadone as well as to initiate such clinical studies of methadone disposition in well-difined patient sub-groups. Studies of methadone concentration in cerebrospinal fluid in patients maintained on methadone have been carried out. Techniques have been developed for the study of methadone and its metabolites in human bile. Studies of the intrahepatic disposition of long- and short-acting narcotics have been carried out using the isolated perfused rabbit liver preparation. Studies of drug interactions between methadone and ethanol, both administered on a chronic basis, have been carried out in the rat. Studies of disulfiram interactions with methadone have been carried out in methadone-maintained subjects. Studies of other potential drug interactions with methadone are in progress.